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Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients
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Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients Juri Kawaguchi (MD)a,b,1, Yasuhiro Hamatani (MD, PhD)a,c,1, Atsushi Hirayama (MD, MPH)a, Kunihiro Nishimura (MD, PhD, MPH)d, Eri Nakai (MD)a,e, Emi Nakamura f, Michi Miyata f, Yukie Kawano (RN)g, Yasuko Takada (RN)g, Yuta Anchi (CPP)a, Sayaka Funabashi (MD)a, Kensuke Kuroda (MD)a, Michiyo Azechi (MD, PhD)h, Hiroyuki Takahama (MD, PhD)a, Toshihisa Anzai (MD, PhD, FJCC)a,i, Satoshi Yasuda (MD, PhD, FJCC)a, Hiroaki Kitaoka (MD, PhD, FJCC)b, Chisato Izumi (MD, PhD, FJCC)a,* a
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University, Kochi, Japan Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan d Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan e Division of Cardiology, Department of Medicine II, Kansai Medical University, Osaka, Japan f Department of Pharmacy, National Cerebral and Cardiovascular Center, Osaka, Japan g Department of Nursing, National Cerebral and Cardiovascular Center, Osaka, Japan h Department of Psychiatry, National Cerebral and Cardiovascular Center, Osaka, Japan i Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 October 2019 Received in revised form 5 December 2019 Accepted 21 December 2019 Available online xxx
Background: In the field of palliative care, morphine is known to be effective for alleviating dyspnea in cancer patients. However, little is known regarding the safety and efficacy of morphine therapy for refractory dyspnea as palliative care in advanced heart failure (HF) patients. Methods: We retrospectively reviewed consecutive advanced HF patients who were referred to the Palliative Care Team at our institution and administered morphine for refractory dyspnea during hospitalization between September 2013 and December 2018. We investigated the details of morphine usage, vital signs, an 11-point quantitative symptom scale, and adverse events at baseline, 24 h, and 72 h after the start of treatment. Results: Morphine was administered for refractory dyspnea in 43 advanced HF patients [mean age: 73.5 years, male: 28 (65%), New York Heart Association functional class IV: 43 (100%), median left ventricular ejection fraction: 25%, median B-type natriuretic peptide level: 927 pg/ml, concurrent intravenous inotrope: 33 (77%)]. Median initial dose of morphine was 5 mg/day in both oral and intravenous administration and median duration of administration was 5 days. Significant decreases in an 11-point quantitative symptom scale [7 (5, 9) vs. 2 (1, 6); p < 0.01, (data available in 8 patients)] and respiratory rate (22.2 6.1 vs. 19.7 5.2 breaths per minute; p < 0.01) were observed 24 h after the start of morphine administration. Meanwhile, oxygen saturation, blood pressure, and heart rate were not significantly altered after treatment (NS). Common adverse events were delirium (18%) and constipation (8%); however, no lethal adverse event definitely related to morphine therapy occurred during treatment. Conclusions: This single-center retrospective study revealed the clinical practice of morphine therapy and suggested that morphine therapy might be feasible for refractory dyspnea as palliative care in advanced HF patients. © 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Morphine Heart failure Palliative care Opioid Dyspnea
* Corresponding author. E-mail address: [email protected] (C. Izumi). 1 Juri Kawaguchi and Yasuhiro Hamatani are co-first authors. https://doi.org/10.1016/j.jjcc.2019.12.015 0914-5087/© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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Introduction Heart failure (HF) is a progressive disease with a poor prognosis and is a major growing public health problem worldwide in the aging society [1–4]. For chronic HF patients, healthcare professionals should focus on not only prolonging survival but also improving their quality of life [5,6]. Patients with chronic HF frequently suffer from dyspnea due to multifactorial mechanisms including pulmonary congestion, low perfusion, and psychological distress. Dyspnea often persists despite optimal HF therapy, and refractory dyspnea severely worsens HF patients’ quality of life, especially in the advanced stage of HF [7]. Therefore, alleviating refractory dyspnea as palliative care is an important issue to improve the quality of life in advanced HF patients. Morphine, which is an opioid, is known to be effective for relief of refractory dyspnea in patients with cancer [8]. The European and Japanese HF guidelines suggest morphine therapy for refractory dyspnea as palliative care in advanced HF patients [9], based on the previous studies which reported the effectiveness of morphine administration for dyspnea in chronic HF patients [10–12]. However, these studies only included stable outpatients who could tolerate a randomized study and/or crossover trial and had a relatively small sample size. To date, the safety and efficacy of morphine therapy for hospitalized advanced HF patients as palliative care in real-world clinical practice have not been clarified. Accordingly, we aimed to investigate the real-world practice of morphine therapy for refractory dyspnea as palliative care in hospitalized advanced HF patients. Methods Study design and population This was a single-center retrospective study conducted by members of the Palliative Care Team (Supplementary Table S1) of the National Cerebral and Cardiovascular Center, which is a tertiary cardiovascular referral center in Japan. Palliative Care Team activities commenced at our institution in September 2013. We retrospectively reviewed consecutive patients who were hospitalized in our institution and were referred to the Palliative Care Team between September 2013 and December 2018. Based on a review of Palliative Care Team consultations, advanced HF patients who were hospitalized for HF and administered morphine for refractory dyspnea as palliative care were included in this analysis. Morphine therapy was preceded by thorough discussion with the multidisciplinary team and attending doctors. The decision to administer morphine to advanced HF patients with intractable severe symptoms that were refractory to ordinary palliative care approaches was finally made by the attending doctors, with consideration of the wishes of the patients and their family members. The decision of administration route was made by the multidisciplinary team and attending doctors based on the patients’ condition and preference. Dose of morphine was determined on case-by-case basis considering the age, physical constitution, renal function, and symptom severity of the patients. We excluded patients who were intubated at the time of morphine administration and those who were administered morphine for symptoms other than dyspnea, such as intractable pain in this study.
including the administration route, dose, and duration. We obtained temporal changes in vital signs including respiratory rate, oxygen saturation, blood pressure, and heart rate [13]. Furthermore, we investigated the efficacy of morphine by retrospectively obtaining quantitative symptom scale data using an 11-point scale (0 = lowest, 10 = highest) from the medical charts. Since morphine was administered mostly within a short period before death at our institution, data of vital signs and symptom scale were obtained before starting treatment and about 24 and 72 h after starting morphine. If the use of morphine was discontinued, we further investigated the reason for discontinuation. Common adverse events of morphine, including nausea, vomiting, constipation, and delirium, at baseline and within 24 and 72 h after starting morphine were retrospectively evaluated by two independent investigators from the descriptions of medical charts. Common adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 4), and those with grade 3 were considered to be unacceptable common adverse events [14,15]. Laboratory data at the time of morphine administration and within 24 and 72 h after starting morphine were obtained. Severe liver dysfunction was defined as newly developed liver enzyme elevation (total bilirubin >3 upper limits of normal, aspartate aminotransferase or alanine aminotransferase >5 upper limits of normal) and severe kidney injury was defined as increase of serum creatinine more than 3 times of baseline level based on the Common Terminology Criteria for Adverse Events (version 4). We investigated the presence of respiratory depression defined as respiratory rate less than 10 breaths per minute [16]. We also obtained data on the patients’ background, echocardiographic data, details of HF treatment, and concomitant drug prescriptions including sedative agents, opioids other than morphine, and prophylactic drugs against morphine’s adverse effects such as laxatives, antiemetic drugs, and antipsychotic agents at the time of morphine administration. This study was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center (M30-162) and conducted according to the Declaration of Helsinki. Statistics Continuous variables were presented as mean standard deviation when normally distributed and as median (interquartile range) when non-normally distributed. Comparison of baseline characteristics between the two groups was made using unpaired Student’s t-test or Mann-Whitney U test for continuous variables, and chi-squared test or Fisher’s exact test for dichotomous variables, when appropriate. Paired t-test was applied to test the difference between variables before and after treatment. Furthermore, mixed-effect models were also applied to test the differences between variables. Missing values were imputed using multiple imputation by chained equations. Twenty imputed data sets were generated and Rubin's rules were used to combine the results. In addition to multiple imputation analysis, complete case analysis was also applied. The Kaplan-Meier method was used to estimate the cumulative incidence of death. All tests were two-tailed, and a value of p < 0.05 was considered statistically significant. All analyses were performed with JMP version 14 (SAS Institute, Cary, NC, USA) and R software (version 3.6.1). Results
Definition and measurements
Baseline characteristics of HF patients who received morphine therapy
We conducted this retrospective study based on a medical chart review. We investigated detailed data on morphine usage
During the study period, a total of 43 advanced HF patients were administered morphine for refractory dyspnea as palliative care
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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Table 1 Baseline characteristics.
Background Age (years) Male sex Body mass index (kg/m2) NYHA functional class IV Period from HF diagnosis (years) Total HF hospitalizations (times) HF hospitalizations within 1 year (times) Left ventricular ejection fraction (%) CRT-D implantation Etiology of HF Ischemic cardiomyopathy Non-ischemic cardiomyopathy Valvular heart disease Others Comorbid conditions Atrial fibrillation Cerebrovascular disease Hypertension Diabetes mellitus Chronic kidney disease Malignancy Oral medication ACE-I/ARB Beta-blocker Mineralocorticoid receptor antagonist Loop diuretic Tolvaptan Digoxin Pimobendan Amiodarone Intravenous treatment Furosemide Carperitide Dobutamine Milrinone Dopamine Laboratory data B-type natriuretic peptide (pg/ml) eGFR (ml/min/1.73 m2) Creatinine (mg/dl) Hemoglobin (g/dl) Total bilirubin (mg/dl) Sodium (mEq/l) Albumin (g/dl)
Total n = 43
Intravenous/subcutaneous n = 26
Oral n = 17
p-Value
73.5 11.4 28 (65%) 20.6 6.7 43 (100%) 7 (2, 17) 5 (2, 8) 2 (1, 3) 25 (15, 40) 10 (23%)
76.7 10.0 15 (58%) 19.4 3.2 26 (100%) 5 (1, 17) 4 (2, 7) 1 (1, 2) 30 (17, 46) 5 (19%)
68.6 12.0 13 (76%) 22.4 9.7 17 (100%) 9 (5, 16) 5 (4, 14) 2 (1, 3) 20 (15, 31) 5 (29%)
0.02 0.33 0.16 1.00 0.32 0.07 0.12 0.11 0.44
11 (26%) 17 (39%) 10 (23%) 5 (12%)
9 8 7 2
2 9 3 3
(12%) (53%) (18%) (18%)
0.20
24 (56%) 11 (26%) 21 (49%) 17 (40%) 32 (74%) 7 (16%)
14 (54%) 7 (27%) 14 (54%) 12 (46%) 19 (73%) 6 (23%)
10 (59%) 4 (24%) 7 (41%) 5 (29%) 13 (76%) 1 (6%)
0.75 1.00 0.42 0.27 1.00 0.21
9 (21%) 9 (21%) 22 (51%) 31 (72%) 20 (47%) 7 (16%) 24 (56%) 9 (21%)
4 (15%) 4 (15%) 12 (46%) 19 (73%) 9 (35%) 3 (12%) 10 (38%) 3 (12%)
5 (29%) 5 (29%) 10 (59%) 12 (71%) 11 (65%) 4 (24%) 14 (82%) 6 (35%)
0.44 0.44 0.42 0.86 0.05 0.41 <0.01 0.12
22 (51%) 10 (23%) 31 (72%) 8 (19%) 8 (19%)
12 (46%) 7 (27%) 19 (73%) 3 (12%) 6 (23%)
10 (59%) 3 (18%) 12 (71%) 5 (29%) 2 (12%)
0.42 0.71 0.86 0.23 0.45
927 (584, 1800) 23.6 (11.6, 37.2) 2.1 (1.4, 4.2) 10.2 1.8 1.0 (0.6, 1.6) 136 8 3.0 0.6
887 (584, 1949) 24.3 (12.1, 34.7) 2.1 (1.4, 3.8) 9.9 1.6 1.0 (0.6, 1.6) 137 8 2.9 0.6
1083 (592, 1837) 22.5 (10.3, 41.7) 2.5 (1.4, 4.6) 10.6 2.1 1.0 (0.5, 1.3) 133 7 3.1 0.6
0.80 0.78 0.73 0.23 0.81 0.12 0.37
(35%) (31%) (27%) (8%)
Continuous variables are presented as mean standard deviation or median (interquartile range). Categorical variables are presented as number of patients (%). ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CRT-D, cardiac resynchronization therapy defibrillator; eGFR, estimated glomerular filtration rate; HF, heart failure; NYHA, New York Heart Association.
during hospitalization at our institution. Demographic and clinical characteristics of patients are presented in Table 1. Mean age was 73.5 years, and 28 were male (65%). All patients were classified as New York Heart Association functional class IV, and median left ventricular ejection fraction was 25%. Intravenous inotropes (including dobutamine, milrinone, and dopamine) and intravenous furosemide were concurrently prescribed in 33 (77%) and 22 (51%), respectively. Median plasma B-type natriuretic peptide level [927 (584, 1800) pg/ml] was high and estimated glomerular filtration rate [23.6 (11.6, 37.2) ml/min/1.73 m2] was low at the time of morphine administration in this population.
in Table 1. Patients with oral administration were younger and had a higher prevalence of tolvaptan and pimobendane administration, compared with those with intravenous or subcutaneous administration. Among 17 with oral administration, 9 were switched to intravenous administration, whereas no patient was switched to oral administration from intravenous administration. Median total length of morphine use was 5 (2, 9) days. Initial dose and final dose of morphine administration and concomitant drug administration are shown in Table 2. About 60% of patients were prescribed a sedative agent and 40% were prescribed a prophylactic drug against the adverse effects of morphine.
Details of morphine usage at our institution
Feasibility of morphine therapy for refractory dyspnea in advanced HF patients
During the median hospitalization period of 56 (36, 125) days, median duration from hospital admission date to the date of starting morphine was 45 (24, 113) days. The first administration route of morphine was oral in 17, intravenous in 24, and subcutaneous in 2. Baseline characteristics of patients with oral and with intravenous or subcutaneous administration are shown
The results of vital signs at baseline and after treatment are shown in Fig. 1. Respiratory rate was significantly reduced 24 h after starting morphine administration (p < 0.01). Other vital signs including blood pressure, heart rate, and oxygen saturation were not significantly altered 24 and 72 h after starting morphine.
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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4 Table 2 Morphine usage and concomitant drug use.
Total n = 43 Dose of morphine Initial dose (oral; n = 17), (mg/day) Initial dose (intravenous or subcutaneous; n = 26), (mg/day) Final dose (oral; n = 8), (mg/day) Final dose (intravenous or subcutaneous; n = 35), (mg/day) Concomitant sedative, analgesic, and prophylactic drugs Midazolam Dexmedetomidine Fentanyl Laxative drug Antiemetic drug Antipsychotic agent
5.0 (3.8, 6.3) 5.0 (5.0, 10.0) 5.0 (3.1, 7.5) 7.5 (5.0, 14.0) 10 (23%) 16 (37%) 4 (9%) 19 (44%) 18 (42%) 17 (40%)
Continuous variables are presented as median (interquartile range). Categorical variables are presented as number of patients (%).
Mixed-effect model using multiple imputation for missing data and complete case analysis confirmed the statistical consistencies of these results about the changes of vital signs at baseline and after treatment. Regarding the efficacy of morphine therapy, an
11-point quantitative symptom scale of dyspnea was obtained at baseline and 24 h after the start of treatment in 8 patients (oral 7, intravenous 1). There was a significant reduction in symptom scale [pre: 7 (5, 9) vs. post: 2 (1, 6); p < 0.01) after starting morphine administration, and 7 out of 8 showed improvement of dyspnea symptoms (Fig. 2). An 11-point quantitative symptom scale decreased from 8 to 6 in a patient with intravenous administration and decreased from 7 (5, 10) to 2 (1, 6) (p = 0.02) among 7 patients with oral administration. Adverse events of morphine therapy in advanced HF patients The incidence of common adverse events is shown in Table 3. Common unacceptable adverse events ( grade 3 of Common Terminology Criteria for Adverse Events) within 72 h were delirium (18%) and constipation (8%) in this study. Laboratory data were available in 28 patients within 24 h and in 37 patients within 72 h. No severe liver dysfunction and kidney injury occurred within 24 h after morphine therapy. Within 72 h, there was no severe kidney injury, but 2 severe liver dysfunctions occurred. Two patients (both with intravenous administration) exhibited respiratory depression within about 24 h and the dose of morphine was
Fig. 1. Vital signs at baseline, 24 h, and 72 h after starting morphine administration. (A) Respiratory rate, (B) oxygen saturation, (C) systolic blood pressure, (D) heart rate. bpm, breaths per minute (A); beats per minute (D).
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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Fig. 2. Quantitative symptom scale of dyspnea at baseline and 24 h after starting treatment.
Table 3 Incidence of unacceptable common adverse events after treatment.
Nausea Vomiting Constipation Delirium
Within 24 hours n = 43
Within 72 hours n = 39
0 1 3 5
0 1 3 7
(0%) (2%) (7%) (12%)
(0%) (3%) (8%) (18%)
Categorical variables are presented as number of patients (%).
reduced (from 5 to 4 mg/day, and from 10 to 2 mg/day with administration of naloxone). As a result, respiratory rate improved to more than 10 breaths per minute. Discontinuation of morphine at our institution Among 43 patients, morphine was discontinued in 11. The reasons for discontinuation were as follows: symptom improvement in 1, oversedation in 2 (although one patient seemed to achieve symptom relief by morphine therapy), vomiting in 1, hypotension in 1 (this patient resumed morphine due to recurrence of dyspnea), ineffectiveness in 2, difficulty in continuing oral morphine administration after intravenous palliative sedation in 1, problem with administration route in 1, and unknown in 2. Outcome of patients with morphine administration Among 43 patients, 41 (95%) died during hospitalization for HF. Median duration between starting morphine and in-hospital death was 7 (4, 12) days in the entire cohort, 9 (6, 27) days in patients with oral administration and 6 (3, 10) days in those with intravenous or subcutaneous administration. The Kaplan–Meier survival curve from starting morphine to the time of death is shown in Fig. 3. Discussion In this retrospective survey of morphine therapy for refractory dyspnea as palliative care in real-world HF practice, we found the following results. First, morphine was administered at a relatively low dose and shortly before death. Second, symptom scale significantly decreased in oral administration after starting morphine therapy. Third, blood pressure, heart rate, and oxygen saturation were not significantly altered after treatment within a short-term period; however, a proportion of patients discontinued
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Fig. 3. Kaplan–Meier survival curve from starting morphine to time of death.
morphine and exhibited adverse events. We believe that the experiences reported in this study contribute to a clearer understanding of the use of morphine in advanced HF patients in real-world daily practice. Dose and timing of morphine therapy in real-world advanced HF practice There is a paucity of real-world data about morphine administration for refractory dyspnea in non-cancer diseases including HF. Our survey at a tertiary cardiovascular referral center beyond a 5-year period revealed that morphine was administered to advanced HF patients at a relatively low dose (median initial dose 5 mg/day in both oral and intravenous administration) in contrast to previous randomized controlled trials of oral morphine in HF patients (20 mg/day) [11,17]. It is reported that symptoms of dyspnea require a lower dose of morphine for alleviation than does pain [18]. In fact, several studies including non-cancer disease have shown improvement of dyspnea with low-dose morphine [13,16,19], as was used in our study. Our survey also revealed that morphine was administered shortly before death (median length 7 days) in most cases, as illustrated in Fig. 3, and the duration of morphine use was relatively short (median duration 5 days), suggesting that morphine was mainly administered to terminally ill HF patients in real-world clinical practice. Because of this retrospective study design, we could not address the optimal dose and timing of morphine administration from our survey, and these issues should be further investigated in a future study. Efficacy of morphine for refractory dyspnea in advanced HF patients Opioid therapy is reported to be effective for treatment of dyspnea due to cancer and/or non-cancer disease such as chronic obstructive pulmonary disease [20,21]. The effects of opioids for dyspnea are assumed to be multifactorial, including decreasing respiratory drive, altering central perception, and alleviating anxiety [13]. Opioid therapy may offer hope in refractory dyspnea in advanced HF patients as well. However, trials of the use of opioids for the relief of dyspnea in chronic HF have been relatively small and the results have been conflicting in terms of effectiveness [17,22,23]. These studies investigated about 10–40 chronic HF patients and mainly included stable outpatients. Our study included hospitalized advanced HF patients in real-world practice, and revealed that quantitative symptom scale of dyspnea and
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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respiratory rate significantly decreased, suggesting reliable effectiveness of morphine for the treatment of refractory dyspnea in advanced HF patients. However, the number of patients with quantitative scale data in this study (8 patients, only 19% of the total) was too small. In particular, the efficacy of intravenous administration could not be referred to because of just one case. We had not established the protocol of symptom evaluation during this study period. Although measuring the degree of severe symptoms in terminally ill patients is difficult, more effort should be made to obtain a quantitative symptom scale. Thus, further studies, including high-quality large-scale prospective cohort studies and possibly randomized controlled trials might be warranted to investigate the efficacy of morphine therapy for refractory dyspnea in advanced hospitalized HF patients. Safety of morphine in advanced HF patients Previous studies suggested that opioids were not associated with reduced survival in terminally ill cancer patients [24,25]. Our study in HF patients also revealed that an opioid did not significantly affect vital signs including blood pressure, heart rate, and oxygen saturation at least within 72 h, suggesting the shortterm safety of morphine administration in HF patients. Adverse events including respiratory depression, nausea, vomiting, constipation, and delirium are often experienced in cancer patients with morphine treatment [26]. In our study, 2 patients exhibited respiratory depression within about 24 h albeit at doses of 5 and 10 mg/day with intravenous administration, reminding us of the importance of considering the possibility of respiratory depression even with a relatively low dose in HF patients. Our study also found that adverse events such as delirium and constipation occurred to some extent, although these symptoms could be due to the terminal disease itself. Severe liver dysfunctions occurred in some patients, although these also might be due to the terminal disease itself. In our survey, prophylactic drugs were prescribed in less than half of the entire cohort, although this was partly due to the terminal stage of the patients.
Conclusion This single-center retrospective study suggested that low-dose morphine might be feasible for the treatment of refractory dyspnea in advanced HF patients. Nevertheless, further studies are strongly warranted to evaluate the efficacy and safety of morphine therapy, and morphine administration must be discussed by a multidisciplinary team. Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors. Disclosures The authors declare that there is no conflict of interest. Acknowledgments The authors are grateful for the contributions of the Palliative Care Team of the National Cerebral and Cardiovascular Center (Kenta Minagawa, Kayoko Enomoto, Kohei Nagamatsu, Yukio Yamamoto, Kyoko Hirakawa, Kohei Kaneta, and Shoko Nakagawa), Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center Research Institute (Shunsuke Murata), the Division of Heart Failure, National Cerebral and Cardiovascular Center (Kenji Moriuchi, Masashi Amano, Atsushi Okada, Makoto Amaki, Takuya Hasegawa, and Hideaki Kanzaki), and all the medical staff involved in this study.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jjcc.2019.12.015.
Study limitations
References
This study had several limitations. First, this was a single-center retrospective study with a relatively small sample size, so it was subject to various biases inherent in such data. Moreover, as mentioned above, the number of patients evaluated using a quantitative symptom scale was too small. Second, patients were recruited from one Japanese national cardiovascular center and referred to the Palliative Care Team at our institution. Therefore, its generalizability is limited. Third, the prescription rates of optimal HF medical therapies were low in this study, mainly due to intolerance of these drugs in the advanced stage of HF. Fourth, we judged the adverse events retrospectively based on the description in the medical records. The frequency of adverse events may have been falsely decreased by failure to record all events in the medical records, even though there were unacceptable symptoms. Concerning delirium, we did not routinely perform screening using validated tools, and retrospectively judged the presence of delirium based on the description of medical charts. Fifth, the decision to administer morphine was made by the attending doctors and was also based on the wishes of patients and/or their family members. Clear inclusion/exclusion criteria and protocol for morphine administration could not be demonstrated in this retrospective study. Moreover, the frequency of symptom evaluation and the titration of morphine administration generally depended on attending medical staff and was highly varied among patients during this study period.
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[20] Jennings AL, Davies AN, Higgins JP, Gibbs JS, Broadley KE. A systematic review of the use of opioids in the management of dyspnoea. Thorax 2002;57:939–44. [21] Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ 2003;327:523–8. [22] Hochgerner M, Fruhwald FM, Strohscheer I. Opioids for symptomatic therapy of dyspnoea in patients with advanced chronic heart failure–is there evidence? Wien Med Wochenschr 2009;159:577–82. [23] Johnson MJ, Cockayne S, Currow DC, Bell K, Hicks K, Fairhurst C, et al. Oral modified release morphine for breathlessness in chronic heart failure: a randomized placebo-controlled trial. ESC Heart Fail 2019. http://dx.doi.org/ 10.1002/ehf2.12498. [24] Bengoechea I, Gutierrez SG, Vrotsou K, Onaindia MJ, Lopez JM. Opioid use at the end of life and survival in a hospital at home unit. J Palliat Med 2010;13:1079–83. [25] Azoulay D, Jacobs JM, Cialic R, Mor EE, Stessman J. Opioids, survival, and advanced cancer in the hospice setting. J Am Med Dir Assoc 2011;12:129–34. [26] Corli O, Floriani I, Roberto A, Montanari M, Galli F, Greco MT, et al. Are strong opioids equally effective and safe in the treatment of chronic cancer pain? A multicenter randomized phase IV ‘real life’ trial on the variability of response to opioids. Ann Oncol 2016;27:1107–15.
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Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients Juri Kawaguchi (MD)a,b,1, Yasuhiro Hamatani (MD, PhD)a,c,1, Atsushi Hirayama (MD, MPH)a, Kunihiro Nishimura (MD, PhD, MPH)d, Eri Nakai (MD)a,e, Emi Nakamura f, Michi Miyata f, Yukie Kawano (RN)g, Yasuko Takada (RN)g, Yuta Anchi (CPP)a, Sayaka Funabashi (MD)a, Kensuke Kuroda (MD)a, Michiyo Azechi (MD, PhD)h, Hiroyuki Takahama (MD, PhD)a, Toshihisa Anzai (MD, PhD, FJCC)a,i, Satoshi Yasuda (MD, PhD, FJCC)a, Hiroaki Kitaoka (MD, PhD, FJCC)b, Chisato Izumi (MD, PhD, FJCC)a,* a
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan Department of Cardiology and Geriatrics, Kochi Medical School, Kochi University, Kochi, Japan Department of Cardiology, National Hospital Organization Kyoto Medical Center, Kyoto, Japan d Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan e Division of Cardiology, Department of Medicine II, Kansai Medical University, Osaka, Japan f Department of Pharmacy, National Cerebral and Cardiovascular Center, Osaka, Japan g Department of Nursing, National Cerebral and Cardiovascular Center, Osaka, Japan h Department of Psychiatry, National Cerebral and Cardiovascular Center, Osaka, Japan i Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan b c
A R T I C L E I N F O
A B S T R A C T
Article history: Received 1 October 2019 Received in revised form 5 December 2019 Accepted 21 December 2019 Available online xxx
Background: In the field of palliative care, morphine is known to be effective for alleviating dyspnea in cancer patients. However, little is known regarding the safety and efficacy of morphine therapy for refractory dyspnea as palliative care in advanced heart failure (HF) patients. Methods: We retrospectively reviewed consecutive advanced HF patients who were referred to the Palliative Care Team at our institution and administered morphine for refractory dyspnea during hospitalization between September 2013 and December 2018. We investigated the details of morphine usage, vital signs, an 11-point quantitative symptom scale, and adverse events at baseline, 24 h, and 72 h after the start of treatment. Results: Morphine was administered for refractory dyspnea in 43 advanced HF patients [mean age: 73.5 years, male: 28 (65%), New York Heart Association functional class IV: 43 (100%), median left ventricular ejection fraction: 25%, median B-type natriuretic peptide level: 927 pg/ml, concurrent intravenous inotrope: 33 (77%)]. Median initial dose of morphine was 5 mg/day in both oral and intravenous administration and median duration of administration was 5 days. Significant decreases in an 11-point quantitative symptom scale [7 (5, 9) vs. 2 (1, 6); p < 0.01, (data available in 8 patients)] and respiratory rate (22.2 6.1 vs. 19.7 5.2 breaths per minute; p < 0.01) were observed 24 h after the start of morphine administration. Meanwhile, oxygen saturation, blood pressure, and heart rate were not significantly altered after treatment (NS). Common adverse events were delirium (18%) and constipation (8%); however, no lethal adverse event definitely related to morphine therapy occurred during treatment. Conclusions: This single-center retrospective study revealed the clinical practice of morphine therapy and suggested that morphine therapy might be feasible for refractory dyspnea as palliative care in advanced HF patients. © 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Keywords: Morphine Heart failure Palliative care Opioid Dyspnea
* Corresponding author. E-mail address: [email protected] (C. Izumi). 1 Juri Kawaguchi and Yasuhiro Hamatani are co-first authors. https://doi.org/10.1016/j.jjcc.2019.12.015 0914-5087/© 2020 Published by Elsevier Ltd on behalf of Japanese College of Cardiology.
Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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Introduction Heart failure (HF) is a progressive disease with a poor prognosis and is a major growing public health problem worldwide in the aging society [1–4]. For chronic HF patients, healthcare professionals should focus on not only prolonging survival but also improving their quality of life [5,6]. Patients with chronic HF frequently suffer from dyspnea due to multifactorial mechanisms including pulmonary congestion, low perfusion, and psychological distress. Dyspnea often persists despite optimal HF therapy, and refractory dyspnea severely worsens HF patients’ quality of life, especially in the advanced stage of HF [7]. Therefore, alleviating refractory dyspnea as palliative care is an important issue to improve the quality of life in advanced HF patients. Morphine, which is an opioid, is known to be effective for relief of refractory dyspnea in patients with cancer [8]. The European and Japanese HF guidelines suggest morphine therapy for refractory dyspnea as palliative care in advanced HF patients [9], based on the previous studies which reported the effectiveness of morphine administration for dyspnea in chronic HF patients [10–12]. However, these studies only included stable outpatients who could tolerate a randomized study and/or crossover trial and had a relatively small sample size. To date, the safety and efficacy of morphine therapy for hospitalized advanced HF patients as palliative care in real-world clinical practice have not been clarified. Accordingly, we aimed to investigate the real-world practice of morphine therapy for refractory dyspnea as palliative care in hospitalized advanced HF patients. Methods Study design and population This was a single-center retrospective study conducted by members of the Palliative Care Team (Supplementary Table S1) of the National Cerebral and Cardiovascular Center, which is a tertiary cardiovascular referral center in Japan. Palliative Care Team activities commenced at our institution in September 2013. We retrospectively reviewed consecutive patients who were hospitalized in our institution and were referred to the Palliative Care Team between September 2013 and December 2018. Based on a review of Palliative Care Team consultations, advanced HF patients who were hospitalized for HF and administered morphine for refractory dyspnea as palliative care were included in this analysis. Morphine therapy was preceded by thorough discussion with the multidisciplinary team and attending doctors. The decision to administer morphine to advanced HF patients with intractable severe symptoms that were refractory to ordinary palliative care approaches was finally made by the attending doctors, with consideration of the wishes of the patients and their family members. The decision of administration route was made by the multidisciplinary team and attending doctors based on the patients’ condition and preference. Dose of morphine was determined on case-by-case basis considering the age, physical constitution, renal function, and symptom severity of the patients. We excluded patients who were intubated at the time of morphine administration and those who were administered morphine for symptoms other than dyspnea, such as intractable pain in this study.
including the administration route, dose, and duration. We obtained temporal changes in vital signs including respiratory rate, oxygen saturation, blood pressure, and heart rate [13]. Furthermore, we investigated the efficacy of morphine by retrospectively obtaining quantitative symptom scale data using an 11-point scale (0 = lowest, 10 = highest) from the medical charts. Since morphine was administered mostly within a short period before death at our institution, data of vital signs and symptom scale were obtained before starting treatment and about 24 and 72 h after starting morphine. If the use of morphine was discontinued, we further investigated the reason for discontinuation. Common adverse events of morphine, including nausea, vomiting, constipation, and delirium, at baseline and within 24 and 72 h after starting morphine were retrospectively evaluated by two independent investigators from the descriptions of medical charts. Common adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 4), and those with grade 3 were considered to be unacceptable common adverse events [14,15]. Laboratory data at the time of morphine administration and within 24 and 72 h after starting morphine were obtained. Severe liver dysfunction was defined as newly developed liver enzyme elevation (total bilirubin >3 upper limits of normal, aspartate aminotransferase or alanine aminotransferase >5 upper limits of normal) and severe kidney injury was defined as increase of serum creatinine more than 3 times of baseline level based on the Common Terminology Criteria for Adverse Events (version 4). We investigated the presence of respiratory depression defined as respiratory rate less than 10 breaths per minute [16]. We also obtained data on the patients’ background, echocardiographic data, details of HF treatment, and concomitant drug prescriptions including sedative agents, opioids other than morphine, and prophylactic drugs against morphine’s adverse effects such as laxatives, antiemetic drugs, and antipsychotic agents at the time of morphine administration. This study was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center (M30-162) and conducted according to the Declaration of Helsinki. Statistics Continuous variables were presented as mean standard deviation when normally distributed and as median (interquartile range) when non-normally distributed. Comparison of baseline characteristics between the two groups was made using unpaired Student’s t-test or Mann-Whitney U test for continuous variables, and chi-squared test or Fisher’s exact test for dichotomous variables, when appropriate. Paired t-test was applied to test the difference between variables before and after treatment. Furthermore, mixed-effect models were also applied to test the differences between variables. Missing values were imputed using multiple imputation by chained equations. Twenty imputed data sets were generated and Rubin's rules were used to combine the results. In addition to multiple imputation analysis, complete case analysis was also applied. The Kaplan-Meier method was used to estimate the cumulative incidence of death. All tests were two-tailed, and a value of p < 0.05 was considered statistically significant. All analyses were performed with JMP version 14 (SAS Institute, Cary, NC, USA) and R software (version 3.6.1). Results
Definition and measurements
Baseline characteristics of HF patients who received morphine therapy
We conducted this retrospective study based on a medical chart review. We investigated detailed data on morphine usage
During the study period, a total of 43 advanced HF patients were administered morphine for refractory dyspnea as palliative care
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Table 1 Baseline characteristics.
Background Age (years) Male sex Body mass index (kg/m2) NYHA functional class IV Period from HF diagnosis (years) Total HF hospitalizations (times) HF hospitalizations within 1 year (times) Left ventricular ejection fraction (%) CRT-D implantation Etiology of HF Ischemic cardiomyopathy Non-ischemic cardiomyopathy Valvular heart disease Others Comorbid conditions Atrial fibrillation Cerebrovascular disease Hypertension Diabetes mellitus Chronic kidney disease Malignancy Oral medication ACE-I/ARB Beta-blocker Mineralocorticoid receptor antagonist Loop diuretic Tolvaptan Digoxin Pimobendan Amiodarone Intravenous treatment Furosemide Carperitide Dobutamine Milrinone Dopamine Laboratory data B-type natriuretic peptide (pg/ml) eGFR (ml/min/1.73 m2) Creatinine (mg/dl) Hemoglobin (g/dl) Total bilirubin (mg/dl) Sodium (mEq/l) Albumin (g/dl)
Total n = 43
Intravenous/subcutaneous n = 26
Oral n = 17
p-Value
73.5 11.4 28 (65%) 20.6 6.7 43 (100%) 7 (2, 17) 5 (2, 8) 2 (1, 3) 25 (15, 40) 10 (23%)
76.7 10.0 15 (58%) 19.4 3.2 26 (100%) 5 (1, 17) 4 (2, 7) 1 (1, 2) 30 (17, 46) 5 (19%)
68.6 12.0 13 (76%) 22.4 9.7 17 (100%) 9 (5, 16) 5 (4, 14) 2 (1, 3) 20 (15, 31) 5 (29%)
0.02 0.33 0.16 1.00 0.32 0.07 0.12 0.11 0.44
11 (26%) 17 (39%) 10 (23%) 5 (12%)
9 8 7 2
2 9 3 3
(12%) (53%) (18%) (18%)
0.20
24 (56%) 11 (26%) 21 (49%) 17 (40%) 32 (74%) 7 (16%)
14 (54%) 7 (27%) 14 (54%) 12 (46%) 19 (73%) 6 (23%)
10 (59%) 4 (24%) 7 (41%) 5 (29%) 13 (76%) 1 (6%)
0.75 1.00 0.42 0.27 1.00 0.21
9 (21%) 9 (21%) 22 (51%) 31 (72%) 20 (47%) 7 (16%) 24 (56%) 9 (21%)
4 (15%) 4 (15%) 12 (46%) 19 (73%) 9 (35%) 3 (12%) 10 (38%) 3 (12%)
5 (29%) 5 (29%) 10 (59%) 12 (71%) 11 (65%) 4 (24%) 14 (82%) 6 (35%)
0.44 0.44 0.42 0.86 0.05 0.41 <0.01 0.12
22 (51%) 10 (23%) 31 (72%) 8 (19%) 8 (19%)
12 (46%) 7 (27%) 19 (73%) 3 (12%) 6 (23%)
10 (59%) 3 (18%) 12 (71%) 5 (29%) 2 (12%)
0.42 0.71 0.86 0.23 0.45
927 (584, 1800) 23.6 (11.6, 37.2) 2.1 (1.4, 4.2) 10.2 1.8 1.0 (0.6, 1.6) 136 8 3.0 0.6
887 (584, 1949) 24.3 (12.1, 34.7) 2.1 (1.4, 3.8) 9.9 1.6 1.0 (0.6, 1.6) 137 8 2.9 0.6
1083 (592, 1837) 22.5 (10.3, 41.7) 2.5 (1.4, 4.6) 10.6 2.1 1.0 (0.5, 1.3) 133 7 3.1 0.6
0.80 0.78 0.73 0.23 0.81 0.12 0.37
(35%) (31%) (27%) (8%)
Continuous variables are presented as mean standard deviation or median (interquartile range). Categorical variables are presented as number of patients (%). ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CRT-D, cardiac resynchronization therapy defibrillator; eGFR, estimated glomerular filtration rate; HF, heart failure; NYHA, New York Heart Association.
during hospitalization at our institution. Demographic and clinical characteristics of patients are presented in Table 1. Mean age was 73.5 years, and 28 were male (65%). All patients were classified as New York Heart Association functional class IV, and median left ventricular ejection fraction was 25%. Intravenous inotropes (including dobutamine, milrinone, and dopamine) and intravenous furosemide were concurrently prescribed in 33 (77%) and 22 (51%), respectively. Median plasma B-type natriuretic peptide level [927 (584, 1800) pg/ml] was high and estimated glomerular filtration rate [23.6 (11.6, 37.2) ml/min/1.73 m2] was low at the time of morphine administration in this population.
in Table 1. Patients with oral administration were younger and had a higher prevalence of tolvaptan and pimobendane administration, compared with those with intravenous or subcutaneous administration. Among 17 with oral administration, 9 were switched to intravenous administration, whereas no patient was switched to oral administration from intravenous administration. Median total length of morphine use was 5 (2, 9) days. Initial dose and final dose of morphine administration and concomitant drug administration are shown in Table 2. About 60% of patients were prescribed a sedative agent and 40% were prescribed a prophylactic drug against the adverse effects of morphine.
Details of morphine usage at our institution
Feasibility of morphine therapy for refractory dyspnea in advanced HF patients
During the median hospitalization period of 56 (36, 125) days, median duration from hospital admission date to the date of starting morphine was 45 (24, 113) days. The first administration route of morphine was oral in 17, intravenous in 24, and subcutaneous in 2. Baseline characteristics of patients with oral and with intravenous or subcutaneous administration are shown
The results of vital signs at baseline and after treatment are shown in Fig. 1. Respiratory rate was significantly reduced 24 h after starting morphine administration (p < 0.01). Other vital signs including blood pressure, heart rate, and oxygen saturation were not significantly altered 24 and 72 h after starting morphine.
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4 Table 2 Morphine usage and concomitant drug use.
Total n = 43 Dose of morphine Initial dose (oral; n = 17), (mg/day) Initial dose (intravenous or subcutaneous; n = 26), (mg/day) Final dose (oral; n = 8), (mg/day) Final dose (intravenous or subcutaneous; n = 35), (mg/day) Concomitant sedative, analgesic, and prophylactic drugs Midazolam Dexmedetomidine Fentanyl Laxative drug Antiemetic drug Antipsychotic agent
5.0 (3.8, 6.3) 5.0 (5.0, 10.0) 5.0 (3.1, 7.5) 7.5 (5.0, 14.0) 10 (23%) 16 (37%) 4 (9%) 19 (44%) 18 (42%) 17 (40%)
Continuous variables are presented as median (interquartile range). Categorical variables are presented as number of patients (%).
Mixed-effect model using multiple imputation for missing data and complete case analysis confirmed the statistical consistencies of these results about the changes of vital signs at baseline and after treatment. Regarding the efficacy of morphine therapy, an
11-point quantitative symptom scale of dyspnea was obtained at baseline and 24 h after the start of treatment in 8 patients (oral 7, intravenous 1). There was a significant reduction in symptom scale [pre: 7 (5, 9) vs. post: 2 (1, 6); p < 0.01) after starting morphine administration, and 7 out of 8 showed improvement of dyspnea symptoms (Fig. 2). An 11-point quantitative symptom scale decreased from 8 to 6 in a patient with intravenous administration and decreased from 7 (5, 10) to 2 (1, 6) (p = 0.02) among 7 patients with oral administration. Adverse events of morphine therapy in advanced HF patients The incidence of common adverse events is shown in Table 3. Common unacceptable adverse events ( grade 3 of Common Terminology Criteria for Adverse Events) within 72 h were delirium (18%) and constipation (8%) in this study. Laboratory data were available in 28 patients within 24 h and in 37 patients within 72 h. No severe liver dysfunction and kidney injury occurred within 24 h after morphine therapy. Within 72 h, there was no severe kidney injury, but 2 severe liver dysfunctions occurred. Two patients (both with intravenous administration) exhibited respiratory depression within about 24 h and the dose of morphine was
Fig. 1. Vital signs at baseline, 24 h, and 72 h after starting morphine administration. (A) Respiratory rate, (B) oxygen saturation, (C) systolic blood pressure, (D) heart rate. bpm, breaths per minute (A); beats per minute (D).
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Fig. 2. Quantitative symptom scale of dyspnea at baseline and 24 h after starting treatment.
Table 3 Incidence of unacceptable common adverse events after treatment.
Nausea Vomiting Constipation Delirium
Within 24 hours n = 43
Within 72 hours n = 39
0 1 3 5
0 1 3 7
(0%) (2%) (7%) (12%)
(0%) (3%) (8%) (18%)
Categorical variables are presented as number of patients (%).
reduced (from 5 to 4 mg/day, and from 10 to 2 mg/day with administration of naloxone). As a result, respiratory rate improved to more than 10 breaths per minute. Discontinuation of morphine at our institution Among 43 patients, morphine was discontinued in 11. The reasons for discontinuation were as follows: symptom improvement in 1, oversedation in 2 (although one patient seemed to achieve symptom relief by morphine therapy), vomiting in 1, hypotension in 1 (this patient resumed morphine due to recurrence of dyspnea), ineffectiveness in 2, difficulty in continuing oral morphine administration after intravenous palliative sedation in 1, problem with administration route in 1, and unknown in 2. Outcome of patients with morphine administration Among 43 patients, 41 (95%) died during hospitalization for HF. Median duration between starting morphine and in-hospital death was 7 (4, 12) days in the entire cohort, 9 (6, 27) days in patients with oral administration and 6 (3, 10) days in those with intravenous or subcutaneous administration. The Kaplan–Meier survival curve from starting morphine to the time of death is shown in Fig. 3. Discussion In this retrospective survey of morphine therapy for refractory dyspnea as palliative care in real-world HF practice, we found the following results. First, morphine was administered at a relatively low dose and shortly before death. Second, symptom scale significantly decreased in oral administration after starting morphine therapy. Third, blood pressure, heart rate, and oxygen saturation were not significantly altered after treatment within a short-term period; however, a proportion of patients discontinued
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Fig. 3. Kaplan–Meier survival curve from starting morphine to time of death.
morphine and exhibited adverse events. We believe that the experiences reported in this study contribute to a clearer understanding of the use of morphine in advanced HF patients in real-world daily practice. Dose and timing of morphine therapy in real-world advanced HF practice There is a paucity of real-world data about morphine administration for refractory dyspnea in non-cancer diseases including HF. Our survey at a tertiary cardiovascular referral center beyond a 5-year period revealed that morphine was administered to advanced HF patients at a relatively low dose (median initial dose 5 mg/day in both oral and intravenous administration) in contrast to previous randomized controlled trials of oral morphine in HF patients (20 mg/day) [11,17]. It is reported that symptoms of dyspnea require a lower dose of morphine for alleviation than does pain [18]. In fact, several studies including non-cancer disease have shown improvement of dyspnea with low-dose morphine [13,16,19], as was used in our study. Our survey also revealed that morphine was administered shortly before death (median length 7 days) in most cases, as illustrated in Fig. 3, and the duration of morphine use was relatively short (median duration 5 days), suggesting that morphine was mainly administered to terminally ill HF patients in real-world clinical practice. Because of this retrospective study design, we could not address the optimal dose and timing of morphine administration from our survey, and these issues should be further investigated in a future study. Efficacy of morphine for refractory dyspnea in advanced HF patients Opioid therapy is reported to be effective for treatment of dyspnea due to cancer and/or non-cancer disease such as chronic obstructive pulmonary disease [20,21]. The effects of opioids for dyspnea are assumed to be multifactorial, including decreasing respiratory drive, altering central perception, and alleviating anxiety [13]. Opioid therapy may offer hope in refractory dyspnea in advanced HF patients as well. However, trials of the use of opioids for the relief of dyspnea in chronic HF have been relatively small and the results have been conflicting in terms of effectiveness [17,22,23]. These studies investigated about 10–40 chronic HF patients and mainly included stable outpatients. Our study included hospitalized advanced HF patients in real-world practice, and revealed that quantitative symptom scale of dyspnea and
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respiratory rate significantly decreased, suggesting reliable effectiveness of morphine for the treatment of refractory dyspnea in advanced HF patients. However, the number of patients with quantitative scale data in this study (8 patients, only 19% of the total) was too small. In particular, the efficacy of intravenous administration could not be referred to because of just one case. We had not established the protocol of symptom evaluation during this study period. Although measuring the degree of severe symptoms in terminally ill patients is difficult, more effort should be made to obtain a quantitative symptom scale. Thus, further studies, including high-quality large-scale prospective cohort studies and possibly randomized controlled trials might be warranted to investigate the efficacy of morphine therapy for refractory dyspnea in advanced hospitalized HF patients. Safety of morphine in advanced HF patients Previous studies suggested that opioids were not associated with reduced survival in terminally ill cancer patients [24,25]. Our study in HF patients also revealed that an opioid did not significantly affect vital signs including blood pressure, heart rate, and oxygen saturation at least within 72 h, suggesting the shortterm safety of morphine administration in HF patients. Adverse events including respiratory depression, nausea, vomiting, constipation, and delirium are often experienced in cancer patients with morphine treatment [26]. In our study, 2 patients exhibited respiratory depression within about 24 h albeit at doses of 5 and 10 mg/day with intravenous administration, reminding us of the importance of considering the possibility of respiratory depression even with a relatively low dose in HF patients. Our study also found that adverse events such as delirium and constipation occurred to some extent, although these symptoms could be due to the terminal disease itself. Severe liver dysfunctions occurred in some patients, although these also might be due to the terminal disease itself. In our survey, prophylactic drugs were prescribed in less than half of the entire cohort, although this was partly due to the terminal stage of the patients.
Conclusion This single-center retrospective study suggested that low-dose morphine might be feasible for the treatment of refractory dyspnea in advanced HF patients. Nevertheless, further studies are strongly warranted to evaluate the efficacy and safety of morphine therapy, and morphine administration must be discussed by a multidisciplinary team. Funding This research received no grant from any funding agency in the public, commercial, or not-for-profit sectors. Disclosures The authors declare that there is no conflict of interest. Acknowledgments The authors are grateful for the contributions of the Palliative Care Team of the National Cerebral and Cardiovascular Center (Kenta Minagawa, Kayoko Enomoto, Kohei Nagamatsu, Yukio Yamamoto, Kyoko Hirakawa, Kohei Kaneta, and Shoko Nakagawa), Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center Research Institute (Shunsuke Murata), the Division of Heart Failure, National Cerebral and Cardiovascular Center (Kenji Moriuchi, Masashi Amano, Atsushi Okada, Makoto Amaki, Takuya Hasegawa, and Hideaki Kanzaki), and all the medical staff involved in this study.
Appendix A. Supplementary data Supplementary material related to this article can be found, in the online version, at doi:https://doi.org/10.1016/j.jjcc.2019.12.015.
Study limitations
References
This study had several limitations. First, this was a single-center retrospective study with a relatively small sample size, so it was subject to various biases inherent in such data. Moreover, as mentioned above, the number of patients evaluated using a quantitative symptom scale was too small. Second, patients were recruited from one Japanese national cardiovascular center and referred to the Palliative Care Team at our institution. Therefore, its generalizability is limited. Third, the prescription rates of optimal HF medical therapies were low in this study, mainly due to intolerance of these drugs in the advanced stage of HF. Fourth, we judged the adverse events retrospectively based on the description in the medical records. The frequency of adverse events may have been falsely decreased by failure to record all events in the medical records, even though there were unacceptable symptoms. Concerning delirium, we did not routinely perform screening using validated tools, and retrospectively judged the presence of delirium based on the description of medical charts. Fifth, the decision to administer morphine was made by the attending doctors and was also based on the wishes of patients and/or their family members. Clear inclusion/exclusion criteria and protocol for morphine administration could not be demonstrated in this retrospective study. Moreover, the frequency of symptom evaluation and the titration of morphine administration generally depended on attending medical staff and was highly varied among patients during this study period.
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Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015
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Please cite this article in press as: Kawaguchi J, et al. Experience of morphine therapy for refractory dyspnea as palliative care in advanced heart failure patients. J Cardiol (2020), https://doi.org/10.1016/j.jjcc.2019.12.015